Cyanamide derivatives of tetrahydrodibenzo[a, d]cyclooctene



United States Patent CYANAMIDE DERIVATIVES 0F TETRAHYDRO- DIBENZO[a,d]CYCLOOCTENE Edward L. Engelhardt, Gwynedd Valley, and Marcia E. Christy, Colemar, Pa., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Jan. 11, 1963, Ser. No. 250,768

3 Claims. (Cl. 260--551) R H oHgcHqoHiN and A s 5 7 9 X X CHOHQOHHN and the non-toxic acid salts thereof, wherein R represents hydrogen or an alkyl radical having up to 6 carbon atoms, R represents an alkyl radical having up to 6 carbon atoms and X and X are similar or dissimilar and are selected from hydrogen, an alkyl group having up to 6 carbon atoms, an alkenyl group having up to 6 carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, a phenyl or a substituted phenyl radical, an acyl group having up to 4 carbon atoms, a perfluoroacyl group having up to 4 carbon atoms, amino, an alkylamino group having up to 4 carbon atoms, a dialkylamino group having up to 8 carbon atoms, an acylamino group having up to 4 carbon atoms, a perfluoroacylamino group having up to 4 carbon atoms, an alkylsulfonylamino group having up to 4 carbon atoms, halogen (fluorine, chlorine, bromine or iodine), hydroxyl, an alkoxy group having up to 4 carbon atoms, a perfluoroalkoxy group having up to 4 carbon atoms, cyano, carboxy, carbamoyl, an alkylcarbamoyl group having up to 5 carbon atoms, a dialkycarbamoyl group having up to 9 carbon atoms, a carbalkoxy group having up to 6 carbon atoms, mercapto, an alkylmercapto group having up to 4 carbon atoms, a perfluoroalkylmercapto group having up to 4 carbon atoms, an alkylsulfonyl group having up to 4 carbon atoms, a perfluoroalkylsulfonyl group having up to 4 carbon atoms, sulfamoyl, an alkylsulfamoyl group having up to 4 carbon atoms, or a dialkylsulfamoyl group having up to 8 carbon atoms. More than one of these substituents may be on each 'benzenoid ring.

Where R and R are each alkyl radicals, they may be similar or dissimilar, either straight or branched chain. They may also be linked together through an atom of carbon, nitrogen or oxygen to form a heterocyclic ring having from S to 6 atoms therein such as l-piperidyl,

pylrrolidyl, 4-morpholinyl and 1-loweralkyl-4-piperazmy Furthermore, the compounds represented above may also have substituents on the propyl or propylidene side chain such as lower alkyl radicals, preferably having from 1 to 4 carbon atoms. Where one or more of the propyl or propylidene hydrogens is substituted by an alkyl group, one of the alkyl substituents can be linked with R to .form a heterocyclic ring including the nitrogen atom.

Representive compounds embraced within the scope of the invention include: 10-chloro-12-[3-(l-methyl-4-piperazinyl) propylidene]- 5,6,7, 12 tetrahydrodibenzo [a,d] cyclooctene 12-(3-dimethylaminopropylidene) 5, 6,7,12-tetrahydrodibenzo [a,d] cyclooctene 12-(3-methylaminopropyl) 5,6,7,IZ-tetrahydrodibenzo- [a,d]cyclooctene 12-(3-dimethylaminopropylidene) 10 methylsulfonyl- 5,6,7 12-tetrahydrodibenzo [a,d] cyclooctene The compounds represented structurally above have been found to possess useful pharmacological properties. In this regard, they can advantageously be employed in pharmaceutical applications particularly because of their tranquilizing and anti-depressant activity. In such usage the compounds may be utilized in their free base or nontoxic acid salt form, the latter generally being preferred. They may be administered orally or parenterally in the form of aqueous solutions or suspensions but they are preferably administered orally in the form of tablets, powders, sustained release pellets and the like. The dosage level of any one of the compounds will, of course, vary over a relatively wide range depending upon the activity of the particular compound employed and its intended use. However, in most instances satisfactory results are obtained at a daily dosage level of from about 15 mg. to about 500 mg., preferably given in divided doses over the day or in sustained release form.

The various methods that have been found to be particularly suitable for preparing the compounds represented structurally hereinabove can be illustrated by the following reaction scheme wherein R is limited to an alkyl radical having up to 6 carbon atoms; Hal represents halogen, preferably chlorine or bromine; and X, X and R are as previously defined:

\ Reduction HI R H CHzCHgCHnN Dehydration -H2O I! II I u CHOP-[QUEEN Reduction X l Dealkylation l Dealkylation wherein Hal represents halogen, preferably chlorine or bromine and X, X and R are as previously designated.

As is readily apparent from the above reaction scheme, a 6,7 dihydrobenzo[a,d]cyclocten-l2-(5H)-one is converted to a tertiary alcohol by reaction with a Grignard reagent, followed by hydrolysis of the resulting Grignard adduct. The Grignard reagent is prepared from the appropriate 3-tertiaryaminopropyl halide in tetrahydrofuran in known manner. The reaction with the Grignard reagent is preferably initially carried out at reduced temperature such as is obtained by the use of an ice-bath and finally may continue at room temperature. It has been found that tetrahydrofuran is an excellent solvent for carrying out the reaction and, accordingly, the ketone may be added directly to the reaction mixture in which the Grignard reagent was prepared. However, any inert solvent for the reactants may be employed. After the addition reaction is completed, the bulk of the solvent is removed by vacuum distillation and hydrolysis of the Grignard adduct carried out in such a way that strongly acidic conditions are avoided. Thus, for example, the Grignard adduct is dissolved in a suitable solvent such as benzene and hydrolyzed by the addition of aqueous ammonium chloride solution with cooling, although water alone may be sufficient. The carbinol is recovered by evaporation of the solvent after separation of any insoluble inorganic material by filtration.

The tertiary alcohol can be directly reduced by reaction with hydrogen iodide, or any reagents that will produce hydrogen iodide in situ, to the 12-(3-tertiaryaminopropyl)- 5,6,7,lZ-tetrahydrodibenzocyclooctene. The reduction of the carbinol is advantageously carried out by dissolving it in a solvent, such as acetic acid, adding the reducing agent and then refluxing until the reaction is completed. A reducing agent for iodine, such as phosphorus or hypophosphorus acid can, if desired, be employed to reconvert the iodine liberated to hydrogen iodide. The desired product is recovered in conventional manner such as by extraction .into a suitable solvent and evaporation of the solvent.

The preparation of the l2-(3-tertiaryaminopropylidene) 5,6,7,12 tetrahydrodibenzo[a,d]cyclooctenes is readily effected by dehydration of the carbinol in a suitable solvent. The dehydration can be effected by known procedures employing known dehydrating agents. Dehydrating agents which have been found especially useful are acetyl chloride, thionyl chloride, acetic anhydride and trifluoroacetic anhydride. Other dehydrating agents as potassium bisulfate, concentrated hydrochloric acid and the like, can also be used. Solvents which are well adapted to the requirements of this step when acetyl chloride or a similar dehydrating agent is employed are chloroform, methylene chloride andtrifluoroacetic acid. The desired olefinic compound is recovered in conventional manner.

The 12- 3-tertiaryaminopropyl -5, 6,7,12-tetrahydrodibenzo[a,d]cyclooctenes can also be prepared by an alternate or hydroboration of the corresponding 12-(3-tertiaryaminopropylidene) 5,6,7,l2 tetrahydrodibenzo[a,d]cyclooctenes can also be prepared by an alternate method which involves catalytic hydrogenation or hydroboration of the corresponding 12-(3-tertiaryaminopropylidene)-5, 6,7,l2-tetrahydrodibenzo[a,d]cyclooctene obtained as described above. These procedures are preferably employed when it is desired to have a nuclear alkoxy substituent because hydrogen iodide employed for the reduction of the carbinol to the corresponding tertiaryaminopropyl derivative will also attack the alkoxy radical. Catalytic hydrogenation may be performed employing palladium, platinum or nickel catalysts by conventional procedures. Hy-

droboration is preferably elfected by treatment of the olefinic compound with diborane and the intermediate borane derivative treated with a fatty acid such as propionic acid, to generate the saturated compound, in the manner described by H. C. Brown and K. Murray, J. Am. Chem. Soc., 81, pp. 41089 (1959).

The preparation of the secondary aminopropyl and secondary aminopropylidene derivatives encompassed within the scope of the invention is effected by dealkylation of the corresponding tertiary amino compounds. Where the preparation of such compounds is contemplated, it is preferred that the alkyl substituents attached to the nitrogen of the tertiary aminopropyl or tertiary aminopropylidene compounds be the same. This is readily accomplished by appropriate selection of the Grignard reagent used to prepare the carbinol from which these tertiary amino compounds are derived. Where it is desired to prepare those secondary aminopropyl and secondary aminopropylidene derivatives having a methyl or ethyl radical attached to the nitrogen atom, dealkylation can be accomplished by condensing the tertiary amino compound with a haloformate to form the corresponding urethane intermediate and the urethane intermediate thus produced subjected to hydrolysis to convert the substituted carbamyl group of the urethane to a hydrogen atom. This process may be represented as follows:

3e one Haloformate HalGOOR" i\/ X f CHCHzCHzN O H CHzCHzCHaN O f t OR OR Hydrolysis CHCHzOHgNHR' H CHQCHQOHZNHRI wherein Hal and R are as previously defined and R" may be alkyl, aralkyl or aryl. However, it will be readily appreciated by those in the art that inasmuch as the R substituent is removed during the dealkylation step, the selection of the particular haloformate will be limited only by its availability and subsequent ease of hydrolysis of the intermediate urethane produced.

While the reaction involving the haloformate can be carried out in the absence of a solvent, it is preferable to employ a solvent. Suitable solvents include the aromatic hydrocarbons such as benzene and toluene, aliphatic hydrocarbons such as heptane and hexane, and the halogen hydrocarbons such as chloroform and carbon tetrachloride. The reaction may be carried out at room temperature, although an elevated temperature is preferred. At the conclusion of the reaction, the urethane is recovered, after removal of impurities, by evaporation of the solvent.

The urethane intermediate thus produced is then subiected to hydrolysis. The hydrolysis may be carried out under either acidic or basic conditions, although the latter are preferred. After completion of the hydrolysis, the desired product is recovered in conventional manner, such as by extraction into a suitable solvent and evaporation of the solvent.

The dealkylation is preferably accomplished by treatment of the tertiary amino compound with a cyanogen halide to form the corresponding cyanamide intermediate and the cyanamide thus produced hydrolyzed to the corresponding secondary amine. This process may be represented as follows:

Hal-0N X l X X@ @X' \H/ 1 OH O H2OH2N\ H CH2OH2CH2N\ ON C N l l I Hydrolysis X X X X H CHCHzCHzNHR' H CHZCHgCHzNHR' The tertiary amine is dissolved in a non-hydroxylic solvent such as benzene or ether and the solution slowly added to a solution of cyanogenhalide in the same solvent, while stirring and permitting the alkyl halide to escape. After the reaction is complete, the basic material is separated by washing with dilute acid and the cyana'mide isolated by evaporating the solvent. The cyanamide is hydrolyzed to the secondary amine in an acidic or alkaline medium, the former being preferred, and the product recovered in conventional manner.

It will be readily appreciated by those skilled in the art that the 12-(-substituted aminopropylidene)-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctenes of the present invention, which are unsymmetrically substituted in the nucleus, exist as geometric isomers. The separation of these isomers can be achieved by conventional techniques. While the mixture of isomers possesses pharmacological activity, in some instances the activity may be greater in one pure isomer than the other.

The 6,7 dihydrodibenzo[a,d] cycloocten 12-(5H)-one employed as a starting material in the preparation of the compounds described herein may be prepared following the procedure described by K. Stach and H. Spingler in Monatsh. Chem. 93, pp. 889-895 (1962). This compound has been further described by C. D. Gutsche et al. in I. Am. Chem Soc. 80, pp. 57565767 (1958). The nuclearly substituted ketones may be prepared in the same manner as described by Stach and Spingler using the appropriate reactants.

The preparation of representative compounds encompassed within the scope of the present invention is described in the following examples which are illustrative only and are not to be construed as in any way limiting the scope of the invention.

EXAMPLE 1.PREPARATION OF THE INTERME- DIATE, 6,7 DI-HYDRODIBENZO[a,d]CYCLOOC- TEN-12-(5H)-ONE [CF. C. D. GUTSCHE ET AL., I. AM. CHEM. SOC. 80, PP. 5766 (1958)] 2-(3-phenylpropyl)-benzoic acid (62 g., 0.258 mole) is added portion-Wise with stirring to 260 g. of polyphos- 6 phoric acid that is heated in an oil-bath at C. The temperature is raised to -130 C. and stirring and heating continued for 7 hours. The reaction mixture then is removed from the oil-bath and before becoming too viscous, it is poured into a slurry of ice and Water. An oily product separates that solidifies. The mixture is extracted with ether, the ether extract is washed with water, then with dilute sodium hydroxide and finally with water, and dried over sodium sulfate. Concentrating the ether solution gives the crystalline product. An analytical sample recrystallized from absolute alcohol melts (typically) at 145.5-147 C.

Analysis.-Calcd. for C H O: C, 86.44; H, 6.35. Found: C, 86.33; H, 6.63.

EXAMPLE 2.-1 2- (3 DIMETHYLAMINOPROPYL 12 HYDROXY-5, 6 ,7, IZ-TETRAHYDRODIBENZO- [a,d] CYCLOOCTENE The Grignard reagent is prepared from dimethylaminopropyl chloride (0.2 mole) and magnesium (0.2 g. atom) in ml. of dry tetrahydrofuran following the method described in US. Patent No. 2,996,503. A 67 ml. portion of this solution is cooled in an ice-bath and stirred while a solution of 8 g. (0.036 mole) of 6,7-dihydrodibenzo[a,d]cycloocten-12-(5H)-one in 25 ml. of tetrahydrofuran is added dropwise. The usual precautions, such as careful drying of the apparatus and maintaining a nitrogen atmosphere, are observed. If the solution does not contain excess Grignard reagent at the end of the reaction, additional Grignard reagent is added until a test for Grignard reagent remains positive. The cooling bath then is removed and the mixture stirred for 2 hours at room temperature. The bulk of the solvent then is removed by distillation under reduced pressure, benzene added to the residue and the Grignard adduct hydrolyzed by slow addition of water with cooling. The benzene layer is separated and the gelatinous residue is extracted with additional portions of benzene. After washing the combined extracts with water, the benzene is distilled and the solid residue is recrystallized from a mixture of alcohol and water yielding, typically, 9.09 g. of crystalline product, M.P. 126128 C. A second recrystallization gives product, M.P. 126.5128 C.

Analysis.-Calcd. for C H NO: C, 81.51; H, 8.80; N. 4.53. Found: C, 81.35; H, 8.59; N, 4.54.

EXAMPLE 3.12 (3 DIMETHYLAMINOPROPYL- IDENE) 5,6,7,12 TETRAHYDRODIBENZO[a,d]

CYCLOOCTENE 12 (3 dimethylaminopropyl) 12 hydroxy-5,6,7,12- tetrahydrodibenzo[a,d]cyclooctene (4.0 g., 0.013 mole) is dissolved in trifluoroacetic acid, 37 .ml. Trifluoroacetic anhydride, 22 ml., is added and the solution is heated to refluxing for 1 hour. The bulk of the liquid then is distilled on a steam-bath under reduced pressure, the residue taken up in water and the mixture made basic with sodium hydroxide solution. The base is extracted into benzene, the extract washed with water and dried over sodium sulfate. After distilling the bulk of the benzene, 3.4 ml. of a 4.13 N solution of hydrogen chloride in benzene is added and the solution evaporated to dryness. After treating with another portion of benzene and again evaporating to dryness, the residue is crystallized from acetone. The product melts (typically) at 178-179 C.

Analysis.-Calcd. for C H N-HCl: C, 76.93; H, 7.99; N, 4.27. Found: C, 76.78; H, 7.69; N, 4.21.

EXAMPLE 4.-12 (3 METHYLAMINOPROPYL)- 5,6,7, 12 TETRAHYDRODIBENZO [a,d]CYCLOOC- TENE A. 12-(3-dimethylaminopropyl) -5,6,7,12-tetrahydr0- dibenzo [a,d] cyclooctene Hydriodic acid, 15 ml. of 55% (S.G. 1.7), is placed in a flask fitted with a nitrogen inlet reaching to the bottom of the flask, thermometer, stirrer and reflux condenser. With a stream of nitrogen passing through the solution, it is heated to 100 C. and decolorized with a few drops of 50% hypophosphorous acid. 12-(3-dimethylaminopropyl)-12-hydroxy 5,6,7,12 tetrahydrodibenzo- [a,d]cyclooctene, 4.0 g. (0.013 mole), red phosphorus, 1.6 g. (0.052 g. atom), and glacial acetic acid, 15 ml., are added and the mixture is stirred and heated to refluxing in a nitrogen atmosphere for hours. The mixture is filtered hot, washing the precipitate with glacial acetic acid. The filtrate is cooled in an ice-bath, covered with a layer of benzene and, with stirring, made basic with 40% aqueous sodium hydroxide. After two reextractions of the aqueous layer, the combined benzene extracts are washed with water. The precipitate, con sisting of a mixture of red phosphorus and crystalline solid, is extracted with three 75 ml. portions of boiling glacial acetic acid and the phosphorus is removed by filtration. The filtrate is evaporated to dryness under reduced pressure and the residual solid suspended in aqueous sodium hydroxide and shaken with benzene. The benzene extract is washed with water and combined with the previously obtained benzene extract. The solvent is evaporated under reduced pressure, leaving the oily base as the residue in a yield of 3.1 g. The hydrochloride is prepared by treating a solution of the base in absolute ethanol with a slight excess of a solution of hydrogen chloride in ethanol. Dilution with several volumes of absolute ether precipitates the crystalline 12-(3-dimethylaminopropyl) 5,6,7,12 tetrahydrodibenzo[a,d]cyclooctene hydrochloride, M.P. 176.5178.5 C. An analytical sample melts at 177.5178.5 C. after recrystallization from a mixture of isopropyl alcohol and ether.

Analysis.-Calcd. tor C H N-HCl: C, 76.45; H, 8.55; N, 4.25. Found: C, 76.23; H, 8.36; N, 4.17.

B. 12 [3- (N-cyano-N-methyl) aminopropyl] -5,6,7,12- tetrahydrodibenzo [a,d] cy clooctene In a system protected by a drying tube and in which a nitrogen atmosphere is maintained, a solution of 1.55 g. (0.0053 mole) of 12 (3-dimethylaminopropyl)-5,6,7,12- tetrahydrodibenzo[a,d]cyclooctene in 10 ml. of benzene is added dropwise to a stirred solution of cyanogen bromide, 1.3 ml. of a 4.88 M solution in benzene, in 2 ml. of benzene. Stirring is continued for 30 minutes and the mixture then allowed to stand at room temperature overnight. A solid separates and is removed by filtration and washed with benzene. Solvent and excess cyanogen bromide are evaporated from the combined filtrate and washings under reduced pressure. The residue is dissolved in benzene and the solution washed with 2 N hydrochloric acid and then with water. Evaporation of the benzene under reduced pressure gives 12-[3-(N-cyano-N-methyl)aminopropyl} 5,6,7 ,17 tetrahydrodibenzo[a,d]cyclooctene as a solid, M.P. 79-85 C., in a yield of 1.45 g. (90%).

pared as in Step B above is dissolved in 30 ml. of glacial acetic acid. Water, 20 ml., and concentrated hydrochloric acid, 3 ml., are added and the mixture is heated to refluxing for 17 hours. The bulk of the solvent is distilled under reduced pressure and the residue is dissolved in 50 ml. of water and the solution extracted with benzene. The aqueous layer is rendered alkaline with sodium hydroxide and the product is extracted into hexane, removing a small amount of insoluble material by filtration. After washing with water and drying over anhydrous sodium sulfate, the hexane is distilled leaving l2-(3-methylaminopropyl)- 5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene as a viscous oily residue in a yield of 1.1 g. (83%). The base is converted to the hydrochloride salt by dissolution in absolute ethanol, addition of a slight excess of a solution of hydrogen chloride in ethanol, and precipitation by the addition of ether. After recrystallization from ethanol-ether and isopropyl alcohol-ether mixtures, the white crystalline hydrochloride melts at 178.5-179.5 C.

Analysis.-Calcd. for C H N-HCl: C, 76.04; H, 8.30; N, 4.43; Cl, 11.23. Found: C, 76.10; H, 8.24; N, 4.30; Cl, 11.41.

We claim: 1. A compound selected from the group consisting of compounds having the structural formulae wherein R is alkyl radical having up to 6 carbon atoms.

2. 12-[3-(N-cyano-N-methyl)-aminopropyl] 5,6,7,12- tetrahydrodibenzo[a,d] cyclooctene.

3. 12-[3-(N-cyano N methyl) aminopropylidene]- 5,6,7,l2-tetrahydrodibenzo[a,d] cyclooctene.

References Cited UNITED STATES PATENTS 6/1959 Rapoport et al 260--285 5/1964 Winthrop et a1. 260-326.81

OTHER REFERENCES Flynn et al.: J. Am. Chem. Soc., vol. 77, pages 3104-3106 (1955).

Houben-Weyl: Methoden der Organischen, Chemie, 4th ed., Band 11/1 (pages 981985, George Thieme Verlag, Stuttgart, Germany (1957).

Provita et al.: J. Med. and Pharm. Chem., vol. 4, No. 2, pages 411 to 415 (1961).

Richters Organic Chemistry, vol. II, pages 1-3, 6 and 2326, P. Blakistons Son & Co., Philadelphia (1912).

Stachs et al.: Monatsh fiir Chemie, vol. 93, pages 896 to 904 (Sept. 10, 1962).

Wright et al.: J. Org. Chem., vol. 26, pages 4057 to 4060 (1961).

JOHN D. RANDOLPH, Primary Examiner.

WALTER A. MODANCE, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 ,337 ,623 August 22 1967 Edward L. Engelhardt et al It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 22 to 28, the formula should appear as shown below instead of as in the patent:

R N H CH CH CH R/ same column 1, lines 31 to 37, the formula should appear as shown below instead of as in the patent:

/R CHCH CH N same column 1 line 53 for "alkoxy" read alkoxyl line 54 for "perfluoroalkoxy" read perfluoroalkoxyl same column 1, line 57, for "dialkycarbamoyl" read dialkylcarbamoyl column 2 lines 48 to S2 the formula should appear as shown below instead of as in the patent:

0 same column 2 line 53 to S8 the formula should appear as shown below instead of as in the patent:

/R HO H2CH2CH2N\R/ same column 2, lines 62 to 68, the formulas should appear as shown below instead of as in the patent:

/R ca CH ca 2 2 2 CHCH Column 3, lines 1 to 7 the formulas should ear b a elow instead of as in the patent; pp as Shown I HCH CH NHR CH NHR H CH CH same column 3, line ll, for "dihydrobenzo" read dihydrodibenzo lines 61 to 63, strike out "12-(3-tertiaryaminopropyl)-5,6,7,12tetrahydrodibenzo[a,d]cyclooctenes can also be prepared by an alternate or hydroboration of the corresponding"; column 4, lines 27 to 32, the formulas should appear as shown below instead of as in the patent:

I CHCH2CH2N(R same column 4 lines 36 to 44 the formulas should appear as shown below instead of as in the patent:

,R CHCH CH N 0 H CH cH cH N 0 oR \OR" same column 4, lines 48 to 53, the formulas should appear as shown below instead of as in the patent:

CHCH CH NHR A H CH CH CH NHR column 5 lines 9 to 14 the formulas should appear as shown below instead of as in the patent:

X X/ X X cHcH cH N(R) cH cH cH N(R) same column 5 lines 19 to 25 the formulas should appear as shown below instead of as in the patent:

CN CN same column 5 lines 29 to 33 the formulas should appear as shown below instead of as in the patent:

CHCH CHN CH cH CH N Q CHCH cH NHR/ H H CH CH NHR/ same column 5 line 45 for "l2(-substituted" read 12-(3- substituted column 7 line 53 for "5 ,6 ,7 ,17" read 5 ,6 ,7 ,l2 column 8 lines 25 to 31, the formulas should appear as shown below instead of as in the patent:

H CH CH CH N HCH CH N Signed and sealed this 17th day of September 1968 (SEAL) Attest:

EDWARD M.FLETCHER,JR.

EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE STRUCTURAL FORMULAE 